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Effect of practolol on left ventricular dimensions during coronary occlusion
EXPERIMENTAL STUDIES
Effect of Practolol on Left Ventricular Dimensions During Coronary Occlusion
JON
LEKVEN,
MD
Oslo, Norway
From the Institute for Experimental Medical Research, University of Oslo, Ullevaal Hospital, Oslo, Norway. This investigation was financially supported by the Norwegian Council on Cardiovascular Diseases, Professor Carl Semb’s Medical Research Fund and J. L. Tiedmann’s Tobakfabrik Joh. H. Andresen’s Medical Fund. Manuscript accepted December 4. 1974. Address for reprints: Jon Lekven. MD, Institute for Experimental Medical Research, Ullevaal Hospital, N-Oslo 1, Norway.
Beta adrenergic blockade has been suggested to improve the myocardial oxygen balance during ischemlc conditions. This investigation was undertaken to examine the effects of practolol, a relatively cardiospecific beta adrenergic blocking agent, on regional myocardial dlmensions and shortenlng during acute coronary arterial occlusion in dogs. Local myocardial dimensions were measured ultrasonically In ischemlc and nonischemic regions of the lefl ventricle. Myocardial dllatatlon and marked reduction in systolic shortening occurred in ischemic regions after occlusion, whereas nonischemic regions were only moderately dilated. Administration of 10 to 20 mg of practolol exerted different effects in the two ventricular regions; myocardial dilatation was reduced and the systolic shortening increased by practolol in fschemlc regions, whereas further dilatation and diminished shortening occurred In nonischemic control regions. Similar resutts were obtained when heart rate was kept constant by atria1 pacing during beta adrenerglc blockade. Thus, practolol improved the function in ischemic ventricular regions, and restored ventricular stroke volume to preocclusion levels, probably as a result of improved myocardial oxygen balance.
Favorable effects of the cardioselective beta adrenergic blocking agent practolol, 4-(2-hydroxy-3-isopropyl amino-propoxy) acetanilide, in patients suffering from acute myocardial infarction have recently been rep0rted.l Although this effect might to some extent be attributed to the antidysrhythmic properties of practolol,2 improvement of the myocardial oxygen balance is suggested from the finding that practolol reduced S-T segment elevation after acute coronary occlusion.3s4 Although beta adrenergic blockade is known to cause an overall reduction in myocardial oxygen consumption,5p6 a concomitant rise in ventricular volume has been demonstrated,7 which might increase myocardial oxygen demands.8 However, little is known about the mechanical events in ischemic myocardial tissue as influenced by beta adrenergic blocking agents. Reduced myocardial oxygen supply leads to myocardial dilatation in end-diastole and reduced myocardial shortening.g Interventions leading to improved myocardial shortening or reduced ischemic dilatation should thus be regarded as favorable for ventricular function. In this investigation the effects of practolol on myocardial shortening and end-diastolic myocardial dilatation in left ventricular regions acutely deprived of coronary blood supply were studied utilizing ultrasonic measurements of local myocardial dimensions.1°
August 1975
The American Journal of CARDIOLDGY
Vdume 36
179
PRACTOLOL AND VENTRiCULARDIMENSIONS DLWNG ISCHEMIA-LEKVEN
TABLE I Hemodynamic Effects of Practolol During Coronary Arterial Occlusion in Nine Dogs (mean values + standard error) During Control LVSP (mm Hg) LVEDP (mm Hg) dP/dt (mm Hg/sec) SV (ml/beat) HR
115 2.0 1480 14.6
(beats/min)
I8 t 70 f 1.2
154i
* = P <0.02; t = P Con;rol = control tricular end-diastolic obtained before and ume.
t t * *
’ 0.3
8
Coronary
Occlusion
p,
109i 7 4.8 i 0.5 1340 i 70 13.2 i 1.0
NS
155k
During Occlusion with Practolol
PZ NS t t x
8
106r 7 7.8 * 0.9 1090 i 50 14.2 + 1.2
t
133
* 5
<0.005; NS = not significant (P >0.05). observations; dP/dt = maximal value of left ventricular pressure rise; HR = heart rate; LVEDP = left venvalue for comparison of paired data pressure: LVSP = left ventricular systolic pressure; P, = probability before and after administration of practolol; SV = stroke volafter coronary occlusion; P, = comparison
TABLE II Effects of Practolol on Regional Myocardial Dimensions (mm) During Coronary Occlusion SM.%,,, _._. ___..
EDMCLdesc Dog
Control
Occlusion
Practolol
Control
Occlusion
1 2 3 4 5
9.50 12.10 10.40 10.70 9.88
10.00 12.95 11.00 11.10 10.45
9.80 12.75 11.00 11.00 10.45
0.65 0.53 0.50 0.45 0.70
0.40 0.20 0.18 0.35 0.20
6 7 8 9
12.05 10.10 9.78 10.66
12.60 10.60 11.03 11.16
12.25 10.60 10.80 11.06
0.65 0.86 0.55 0.50
Mean SEM
10.57 0.31
11.21 0.32
11.08 0.30
0.60 0.04
I-IO.
t
PI p*
_
Practolol _ ______
symbols
and abbreviations
as in Table
11.63 9.85 11.93 11.90 10.55
0.75 0.50 0.65 0.85 -
0.80 0.40 0.75 0.78
0.65 0.30 0.60 0.40 -
11.63 11.45 10.40 10.70
12.05 11.68 10.65 10.88
0.60 0.70 0.35 0.65
0.65 0.85 0.35 0.60
0.32 0.90 0.33 0.45
10.98 0.25
11.24 0.26
0.63 0.05
0.65 0.07
0.49 0.07
11.13 9.35 11.65 11.15 9.80
11.48 9.75 11.85 11.45 10.13
0.10 0.40 0.20 0.20
0.50 0.70 0.28 0.30
11.50 11.20 9.95 10.50
0.25 0.04
‘0.39 0.05
10.69 0.27
Practolol
t
*
NS t
~....
*
~-_~__.___-
by the left anterior descending (desc) and the left cirIn these regions; SEM = standard error of the mean.
I.
Methods
August 1975
Practolol
0.55 0.27 0.25 0.45 0.25
Animal preparation: Twelve healthy mongrel dogs, weighing 17 to 29 kg, were anesthetized by intravenous administration of sodium pentobarbital, 25 mg/kg body weight, followed by maintenance doses of 50 mg at intervals. The heart was exposed through incision in the fifth left intercostal space, and ventilation maintained by a positive pressure respirator (Cyclator Mk. II, British Oxygen Co., London). The left anterior descending coronary artery was dissected free 0.5 to 2 cm from its origin and a ligature placed loosely around the vessel. Instantaneous myocardial dimensions were measured by ultrasonic transmission between two piezoelectric crystals of lead zirconate titanate (0.5 by 1 by 3 mm) sewn into the left ventricular wall 9 to 11 mm apart at a depth of 5 to 8 mm from the epicardial surfacelo; the frequency response was 40 cycles/set. The distance between the elements is called myocardial chord length and represents the resultant movement of the muscle fibers between the elements. Provided that postoperative examination showed that myocardial chord length was
180
Occlusion
Occlusion
* = P ~0.02; t = P <0.005; NS = not significant (P ,0.05). EDMCL = end-diastolic myocardial chord length In regions supplied cumflex (cf) coronary arteries; SMS = systolic myocardial shortening Other
Occlusion t Control
Control _
t
*
SMS,f Occlusion t
Occlusion t
Occlusion t
~~
EDMCLcf
The American Journal of CARDIOLOGY
parallel to the predominating local fiber orientation, high correlation existed between myocardial chord length and thermodilution determinations of left ventricular volume during great variations in ventricular preload and contractility.‘e One pair of elements was placed in the region supplied by the coronary artery to be occluded, and another pair clearly outside this region for control purposes. Left ventricular pressure was measured by a Statham P23Gb transducer connected to a short catheter introduced through the apex, and the first derivative of left ventricular pressure, dP/dt, was continuously recorded from the pressure channel. Phasic blood flow in the ascending aorta was measured by an electromagnetic flowmeter (Nycotron, model 367, Oslo), and left ventricular stroke volume was determined by beat to beat integration of the flow signals. In three dogs heart rate was kept constant by pacing the right atrium (Grass Instruments model S4G) with pulses of 1 msec at an effective voltage of 1.5 to 2.5 v. Experimental procedure: After control observations were recorded, the coronary artery was occluded by a May-
Volume 36
PRACTOLDL AND W
clMENsloNs Dtmw
l6cHEMlA--LMvEN
MCLcf
mm
MCLDesc mm
FIGURE 1. Dog 2. Effects of practolol during occlusion of the left anterior descending coronary artery. Recordings of local myocardiil chord lengths (MCL) in the ventricular region supplied by the occluded left anterior descending coronary artery (Desc) and by the left circumflex coronary artery (Cf), which was not occluded. Upper margin of tracing denotes the enddffstolic myocardiil chord length.
Stroke
volume
ml/beat u t
Occlusion
1
f
Practolol
min
Occlusion Control
Occlusion Prac;olol
Aortic
flow
Vmin
MCLDesc mm
FIGURE 2. Dog 6. Pattern of myocardffl shortening during occlusion of the left anterior descending coronary artery before and after administration of practolol. Local myocardial chord lengths (MCL) were recorded in the ventricular region supplied by the descending artery @SC) and by the nonoccluded left circumflex coronary artery (Cf).
M%f mm
CKec
field clip. Redetermination of ventricular dimensions, pressures and flow was performed 3 to 5 minutes after occlusion. Then 10 to 20 mg of practolol (Eraldin, Imperial Chemical Industries, London) was given intravenously over 1 to 3 minutes, and new determinations were made 10 minutes after administration of practolol. All recordings were made during steady hemodynamic conditions. Immediately after the dogs were killed by administration of an overdose of sodium pentobarbital, Evans blue dye was injected into the coronary artery at the site of former occlusion and colored tissue was isolated and weighed. On average, 34.3 percent of left ventricular weight (range 21.8 to 41.5 percent) had been rendered ischemic by coronary occlusion. Statistical analysis: Each dog served as its own control. Student’s t test for paired data was used to calculate probability values (P).li A value of P >0.05 was regarded as not
statistically significant.
Results Tables I and II present the hemodynamic and dimensional effects of coronary arterial occlusion and
intravenous administration of practolol in nine dogs with spontaneous cardiac rhythm. Effects of coronary occlusion: Occlusion of the left anterior descending coronary artery was followed by marked end-diastolic dilatation in regions supplied by this artery (Fig. 1). Myocardial dilatation also occurred in nonischemic control regions supplied by the left circumflex coronary artery, and left ventricular end-diastolic pressure was increased by 2.8 f 0.5 mm Hg (P
August 1975
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Volume 36
191
PBACTOLOL AN0 VENTBKXJLARDfMENStONSDURING ISCNEMIA-LEKVEN
15
n EDMCLDesc mm
% of control
12
value
6
10.00 1.00 SMSDesc mm 075
12 n EDMCL Ct % of cant rol
0.25
9
value
-
6 o-
1
I
Control
Occlusion
I
Occlusion Prac:olol
FIGURE 3. Effects of practolol during occlusion of the left anterior descending coronary artery in three dogs with a heart rate kept constant by right atrial pacing. End-diastolic myocardial chord length (EDMCL) and systolic myocardial shortening (SMS) were measured in ventricular regions supplied by the anterior descending artery (Desc).
0 LEFT
3
6
VENTRICULAR
PRESSURE,
9
12
END-DIASTOLIC
mm Hg
occlusion in most of the experiments (Fig. 1). In nonischemic control regions the systolic myocardial shortening remained unchanged during occlusion. Left uentricular performance was reduced by coronary occlusion, as evidenced by lower values for stroke volume, cardiac output, dP/dt and left ventricular systolic pressure (Table I). Effects of practolol: With the coronary artery still occluded, administration of practolol restored stroke volume almost to control levels, although dP/dt was further reduced (Table I). End-diastolic ventricular dimensions in nonischemic regions-and the end-diastolic ventricular pressure-increased further from the values obtained during occlusion alone, whereas the ischemic myocardial dilatation in occluded areas was reduced; however, control levels were not regained during beta adrenergic blockade in any experiment. Practolol diminished the early diastolic myocardial shortening in occluded areas, and a significantly greater portion of shortening occurred in ventricular systole (Fig. 2). In nonischemic regions practolol gave an opposite effect by reducing systolic myocardial shortening (Table II).
Left ventricular systolic pressure remained unchanged during beta adrenergic blockade with practolol. Cardiac output was reduced by 161 f 47 ml/ min (P
182
36
August 1975
The American
Journal of CARDIOLOGY
Volume
FIGURE 4. Relation between left ventricular enddiastolic pressure and changes in end-diastolic myocardial chord length (AEDMCL). A, measurements from ventricular regions supplied by the occluded left anterior descending coronary artery (Desc). B, measurements from control regions supplied by the nonoccluded left circumflex coronary artery (Cf) Open circles = prior to occlusion; closed circles = during occlusion: triangles = after administration of practolol.
PRACTDLDL AND VENTFtWlAR DIMNSIONS DURING ISCI-EMIA-LEKVEN
regions increased by an average of 6.1 f 0.9 percent of control value after coronary occlusion, whereas nonischemic chord length increased by only 2.7 f 0.4 percent (Table II). Although left ventricular end-diastolic pressure was not similarly increased in individual experiments (Fig. 4), the highly significant difference in regional dimensions (P
Discussion Practolol and increased systolic myocardial shortening: The most important finding in this investigation was that practolol increased systolic myocardial shortening, which had been largely reduced by coronary occlusion. Although variable effects of practolol on stroke volume and contractility have previously been reported,4J2 left ventricular dP/dt and systolic myocardial shortening in nonischemic control regions were clearly reduced by practolol in this study. It is therefore reasonable to attribute restoration of stroke volume to an increased myocardial shortening in the ischemic regions. This represents an obvious improvement of ventricular function by practolol during acute coronary occlusion.
Practolol and improved myocardial oxygen balance: It is generally believed that practolol does
not increase myocardial oxygen supplies13 but diminishes net myocardial oxygen requirements through reduction in the contractile state and heart rate,5*6 although an accompanying ventricular dilatation7 might increase the myocardial oxygen demands.* Recent studies314 have revealed that S-T segment changes after coronary occlusion in dogs and myocardial infarction in patients were reduced by practolol, indicating an improved myocardial oxygen balance. Since a close relation between myocardial oxygen consumption and ventricular dilatation has been demonstrated during graded myocardial ischemia,g reduced ischemic dilatation by practolol indicates improved myocardial oxygen balance. A negative chronotropic action of practolol undoubtedly reduces myocardial oxygen demands.* However, since improved function of the ischemic myocardium could be demonstrated during constant atria1 pacing, reduced end-diastolic dimensions and wall tension8pg might also represent a reduction in the myocardial oxygen requirements, thus permitting increased systolic shortening. Thus, in addition to the antidysrhythmic properties of practolol, its ability to improve myocardial oxygen balance through these
End Diastolic Myocardial Dimensions
Left
ventricular
end-diastolic
pressure FIGURE 5. Scheme, calculated from the mean values in Figure 4, of the ventricular pressure/dimension relation in ventricular regions rendered ischemic by coronary arterial occlusion and in nonischemic control regions. Open circles = prior to occlusion; closed circles = during occlusion: triangles = after administration of practolol.
mechanisms constitutes the rationale for use of this agent in patients with acute myocardial infarction.
Practolol and redistribution of blood flow: A relative redistribution
myocardial
of coronary blood flow to ischemic areas has been demonstrated after administration of propranolol to hearts with occluded coronary arteries. l4 If such a mechanism also applies to practolol, this could contribute to improved myocardial oxygen balance and function, mainly in ischemic subendocardial layers. The demonstration in this study that improvement of mechanical function within the ischemic third of the left ventricle after beta adrenergic blockade is associated with concomitant reductions of systolic myocardial shortening within the nonischemic two thirds, ventricular contractility as a whole and dP/dt might be explained by redistribution of myocardial blood flow.
Practolol and improved myocardial metabolism: On the other hand, could myocardial oxygen
balance also be improved by beta adrenergic blocking agents through metabolic mechanisms? It has been demonstrated that antilipolytic agents reduce S-T segment elevation after acute coronary occlusion,15 probably by inhibiting myocardial lipolysis evoked by release of endogenous catecholamines in acutely ischemic tissue16 and leading to a relatively oxygenexpensive consumption of free fatty acids. Antilipolytic activity of practolol has been demonstrated in isolated fat cells17 and, if this applies also to in vivo myocardial oxygen requiremyocardial lipolysis, ments might thus be reduced in acutely ischemic myocardial tissue. Furthermore, it has recently been reportedI* that beta adrenergic blockade with propranolol permitted enhanced glycogenolytic energy production during anoxia in rat hearts. Thus, several mechanisms for improvement of myocardial oxygen balance by beta adrenergic block-
August 1975
The American Journal of CARDIOLOGY
Volume 36
163
PRACTOLOL AND VENTRlCU_AR lX&UONS
DLRING SCHEMIA-LEKVEN
ing agents are proposed although it is not known which is the most important or why oxygen requirements of ischemic myocardial tissue are reduced if increased blood supply may be present. Although these measurements provide no direct information on myocardial oxygen balance, they indicate that the mechanical function of the acutely ischemic myocardium benefits from beta adrenergic blockade by practolol. Practolol and changes in myocardial compliance: Use of left ventricular end-diastolic pressure
measurements to assess cardiac failure has among its limitations dependence on a constant ventricular relation.1gp20 Whereas increased pressure/volume end-diastolic pressure during coronary heart disease is commonly interpreted as an indication of incipient heart failure, the measurements reported here describe a situation after administration of practolol in which improved function of acutely ischemic myocardial tissue is associated with increased ventricular end-diastolic pressure. This finding thus emphasizes the reservations to use of ventricular end-diastolic pressure as a reliable index of ischemia or heart failure. Decreased ventricular compliance has been demonstrated in patients within a few days of myocardial infarction and in patients with chronic coronary artery disease.21 However, the observations in this study suggest an increased ventricular compliance in end-diastole in the ischemic regions immediately
after coronary occlusion. Compliance is defined as dV/dP, where V is volume of the left ventricle and P its intracavitary pressure. Since myocardial chord length increased significantly more within ischemic regions than within control regions, dV/dP must be greater in ischemic areas because the two regions have identical-and increased-ventricular pressures. Although ventricular pressure and dimensions were obtained during steady hemodynamic conditions, they were measured within the time limit of 20 to 30 minutes for development of irreversible cell injury. 22 It is therefore credible that after acute coronary occlusion compliance is initially increased in affected ventricular regions and later decreased, a change that might be explained by the pathologicanatomic alterations and cell death in the early healing phase.23 The observations in this study also indicate that practolol normalizes the increased compliance during acute ischemia. This finding implies that the ischemic myocardial tissue becomes capable of operating a more propitious Frank-Starling curve after beta adrenergic blockade, as was indicated by increased systolic shortening and stroke volume ejection after administration of practolol. Acknowledgment I thank Mrs. Grethe Laerum and Erik Holgersen, engineer, for their skilled technical assistance, and Mrs. Monica Hyde for help in the preparation and typing of the manuscript.
References 1. Jewltt DE, Burgess PA, Shillingford JP: The circulatory effects of practolol (ICI 50 172) in patients with acute myocardial infarction. Cardiovasc Res 4: 188-193, 1970 2. Dunlop D, Shanks RG: Selective blockade of adrenoceptive beta receptors in the heart. Br J Pharmacol Chemother 32: 201-218, 1968 3. Pelldes LJ, Reid DS, Thomas M, et al: Inhibition by &blockade of the ST segment elevation after acute myocardiil infarction in man. Cardiovasc Res 6:295-301, 1972 4. Llbby P, Maroko PR, Covell JW, et al: Effect of practolol on the extent of myocardial ischaemic injury after experimental coronary occlusion and its effects on ventricular function in the normal and ischaemic heart. Cardiovasc Res 7: 167- 173, 1973 5. Epstein SE, Braunwald E: Beta-adrenergic receptor blocking drugs. Mechanisms of action and clinical applications. N Engl J Med275:1106-1112, 1966 6. Ek L, Ablad B: Effects of three beta adrenergic receptor blockers on myocardial oxygen consumption in the dog. Eur J Pharmacol 14:19-28, 1971 7. Chamberlain DA: Effects of beta adrenergic blockade on heart size. Am J Cardiol 18:321-328, 1986 8. Bonnenbllck EH, Ross J Jr, BraunwakJ E: Oxygen consumption of the heart. Newer concepts of its multifactoral determination. Am J Cardiol 22:328-336, 1968 9. Lekven J, Mj#a OD, Kjekshus JK: Compensatory mechanisms during graded myocardial ischemia. Am J Cardiol 31:467-473, 1973 10. Lekven J, Bugge-Asperhelm B, Kill F: Relationship between local myocardial dimensions and left ventricular volume in dogs. Stand J Clin Lab Invest 295-14, 1972 11. Snedeoor GW, Cochran WG: Statistical Methods (sixth adiiion). Ames, Iowa, The Iowa State University Press, 1967, p 59-62 12. Flnegan RE, Marlon AM, Harrlaon DC: Circulatory effects of practolol. Am J Cardiol 29:315-322, 1972
*a4
August 1975
The American Journal of CARDIOLOGY
13. Ross G, Jorgensen CR: Effects of a cardio-selective beta-adrenergic blocking agent on the heart and coronary circulation. Cardiovasc Res 4: 148- 153. 1970 14. Becker L, Pitt B: Regional myocardial blood flow, ischemia and antianginal drugs. Ann Clin Res 3:353-361, 197 1 15. KJekshus JK, Mj+a OD: Effect of inhibition of lipolysis on infarct size after experimental coronary artery occlusion. J Clin Invest 5211770-1778, 1973 16. Wollenberger A, Krause E-G, Shahab L: Endogeneous catecholamine mobilization and the shift to anaerobic energy production in the acutely ischemic myocardium. In. Coronary Circulation and Energetics of the Myocardium (Marchetti G, Taccardi B, ed). Base1 and New York, Karger, 1967. p 200-219 17. Miller DW, Allen Ml: Antilipolytic activity of 4-(2-hydroxy-3-isopropylaminopropoxy) acetanilkie (practolol). Proc Sot Exp Biol Med 136:715-718, 1971 18. Chrlatodoulou J, Smtthen C, Frlschman W, et al: Protective role of increased myocardial glycogen stores induced by propranolol. (abstr). Proceedings VII World Congress of Cardiology, Buenos Aires, 1974. no 136 19. Braunwald E, Ross J Jr: The ventricular end-diastolic pressure. Appraisal of its value in the recognition of ventricular failure in man. Am J Med 34:147-150, 1963 20. Covell JW, Ross J Jr: Nature and significance of alterations in myocardial compliance. Am J Cardiol 32:449-455, 1973 2 I. Mamond 0, Forrester JS: Effect of coronary artery disease and acute myocardial infarction on left ventricular compliance in man. Circulation 45:11-19. 1972 22. Jennings RB: Early phase of myocardial ischemic injury and infarction. Am J Cardiol 24:753-765, 1969 23. Hood WB Jr, Blanc0 JA, Kumar R, et al: Experimental myocardial infarction. IV. Reduction of left ventricular compliance in the healing phase. J Clin Invest 49:1316-1323. 1970
Volume 36
Effect of Practolol on Left Ventricular Dimensions During Coronary Occlusion
JON
LEKVEN,
MD
Oslo, Norway
From the Institute for Experimental Medical Research, University of Oslo, Ullevaal Hospital, Oslo, Norway. This investigation was financially supported by the Norwegian Council on Cardiovascular Diseases, Professor Carl Semb’s Medical Research Fund and J. L. Tiedmann’s Tobakfabrik Joh. H. Andresen’s Medical Fund. Manuscript accepted December 4. 1974. Address for reprints: Jon Lekven. MD, Institute for Experimental Medical Research, Ullevaal Hospital, N-Oslo 1, Norway.
Beta adrenergic blockade has been suggested to improve the myocardial oxygen balance during ischemlc conditions. This investigation was undertaken to examine the effects of practolol, a relatively cardiospecific beta adrenergic blocking agent, on regional myocardial dlmensions and shortenlng during acute coronary arterial occlusion in dogs. Local myocardial dimensions were measured ultrasonically In ischemlc and nonischemic regions of the lefl ventricle. Myocardial dllatatlon and marked reduction in systolic shortening occurred in ischemic regions after occlusion, whereas nonischemic regions were only moderately dilated. Administration of 10 to 20 mg of practolol exerted different effects in the two ventricular regions; myocardial dilatation was reduced and the systolic shortening increased by practolol in fschemlc regions, whereas further dilatation and diminished shortening occurred In nonischemic control regions. Similar resutts were obtained when heart rate was kept constant by atria1 pacing during beta adrenerglc blockade. Thus, practolol improved the function in ischemic ventricular regions, and restored ventricular stroke volume to preocclusion levels, probably as a result of improved myocardial oxygen balance.
Favorable effects of the cardioselective beta adrenergic blocking agent practolol, 4-(2-hydroxy-3-isopropyl amino-propoxy) acetanilide, in patients suffering from acute myocardial infarction have recently been rep0rted.l Although this effect might to some extent be attributed to the antidysrhythmic properties of practolol,2 improvement of the myocardial oxygen balance is suggested from the finding that practolol reduced S-T segment elevation after acute coronary occlusion.3s4 Although beta adrenergic blockade is known to cause an overall reduction in myocardial oxygen consumption,5p6 a concomitant rise in ventricular volume has been demonstrated,7 which might increase myocardial oxygen demands.8 However, little is known about the mechanical events in ischemic myocardial tissue as influenced by beta adrenergic blocking agents. Reduced myocardial oxygen supply leads to myocardial dilatation in end-diastole and reduced myocardial shortening.g Interventions leading to improved myocardial shortening or reduced ischemic dilatation should thus be regarded as favorable for ventricular function. In this investigation the effects of practolol on myocardial shortening and end-diastolic myocardial dilatation in left ventricular regions acutely deprived of coronary blood supply were studied utilizing ultrasonic measurements of local myocardial dimensions.1°
August 1975
The American Journal of CARDIOLDGY
Vdume 36
179
PRACTOLOL AND VENTRiCULARDIMENSIONS DLWNG ISCHEMIA-LEKVEN
TABLE I Hemodynamic Effects of Practolol During Coronary Arterial Occlusion in Nine Dogs (mean values + standard error) During Control LVSP (mm Hg) LVEDP (mm Hg) dP/dt (mm Hg/sec) SV (ml/beat) HR
115 2.0 1480 14.6
(beats/min)
I8 t 70 f 1.2
154i
* = P <0.02; t = P Con;rol = control tricular end-diastolic obtained before and ume.
t t * *
’ 0.3
8
Coronary
Occlusion
p,
109i 7 4.8 i 0.5 1340 i 70 13.2 i 1.0
NS
155k
During Occlusion with Practolol
PZ NS t t x
8
106r 7 7.8 * 0.9 1090 i 50 14.2 + 1.2
t
133
* 5
<0.005; NS = not significant (P >0.05). observations; dP/dt = maximal value of left ventricular pressure rise; HR = heart rate; LVEDP = left venvalue for comparison of paired data pressure: LVSP = left ventricular systolic pressure; P, = probability before and after administration of practolol; SV = stroke volafter coronary occlusion; P, = comparison
TABLE II Effects of Practolol on Regional Myocardial Dimensions (mm) During Coronary Occlusion SM.%,,, _._. ___..
EDMCLdesc Dog
Control
Occlusion
Practolol
Control
Occlusion
1 2 3 4 5
9.50 12.10 10.40 10.70 9.88
10.00 12.95 11.00 11.10 10.45
9.80 12.75 11.00 11.00 10.45
0.65 0.53 0.50 0.45 0.70
0.40 0.20 0.18 0.35 0.20
6 7 8 9
12.05 10.10 9.78 10.66
12.60 10.60 11.03 11.16
12.25 10.60 10.80 11.06
0.65 0.86 0.55 0.50
Mean SEM
10.57 0.31
11.21 0.32
11.08 0.30
0.60 0.04
I-IO.
t
PI p*
_
Practolol _ ______
symbols
and abbreviations
as in Table
11.63 9.85 11.93 11.90 10.55
0.75 0.50 0.65 0.85 -
0.80 0.40 0.75 0.78
0.65 0.30 0.60 0.40 -
11.63 11.45 10.40 10.70
12.05 11.68 10.65 10.88
0.60 0.70 0.35 0.65
0.65 0.85 0.35 0.60
0.32 0.90 0.33 0.45
10.98 0.25
11.24 0.26
0.63 0.05
0.65 0.07
0.49 0.07
11.13 9.35 11.65 11.15 9.80
11.48 9.75 11.85 11.45 10.13
0.10 0.40 0.20 0.20
0.50 0.70 0.28 0.30
11.50 11.20 9.95 10.50
0.25 0.04
‘0.39 0.05
10.69 0.27
Practolol
t
*
NS t
~....
*
~-_~__.___-
by the left anterior descending (desc) and the left cirIn these regions; SEM = standard error of the mean.
I.
Methods
August 1975
Practolol
0.55 0.27 0.25 0.45 0.25
Animal preparation: Twelve healthy mongrel dogs, weighing 17 to 29 kg, were anesthetized by intravenous administration of sodium pentobarbital, 25 mg/kg body weight, followed by maintenance doses of 50 mg at intervals. The heart was exposed through incision in the fifth left intercostal space, and ventilation maintained by a positive pressure respirator (Cyclator Mk. II, British Oxygen Co., London). The left anterior descending coronary artery was dissected free 0.5 to 2 cm from its origin and a ligature placed loosely around the vessel. Instantaneous myocardial dimensions were measured by ultrasonic transmission between two piezoelectric crystals of lead zirconate titanate (0.5 by 1 by 3 mm) sewn into the left ventricular wall 9 to 11 mm apart at a depth of 5 to 8 mm from the epicardial surfacelo; the frequency response was 40 cycles/set. The distance between the elements is called myocardial chord length and represents the resultant movement of the muscle fibers between the elements. Provided that postoperative examination showed that myocardial chord length was
180
Occlusion
Occlusion
* = P ~0.02; t = P <0.005; NS = not significant (P ,0.05). EDMCL = end-diastolic myocardial chord length In regions supplied cumflex (cf) coronary arteries; SMS = systolic myocardial shortening Other
Occlusion t Control
Control _
t
*
SMS,f Occlusion t
Occlusion t
Occlusion t
~~
EDMCLcf
The American Journal of CARDIOLOGY
parallel to the predominating local fiber orientation, high correlation existed between myocardial chord length and thermodilution determinations of left ventricular volume during great variations in ventricular preload and contractility.‘e One pair of elements was placed in the region supplied by the coronary artery to be occluded, and another pair clearly outside this region for control purposes. Left ventricular pressure was measured by a Statham P23Gb transducer connected to a short catheter introduced through the apex, and the first derivative of left ventricular pressure, dP/dt, was continuously recorded from the pressure channel. Phasic blood flow in the ascending aorta was measured by an electromagnetic flowmeter (Nycotron, model 367, Oslo), and left ventricular stroke volume was determined by beat to beat integration of the flow signals. In three dogs heart rate was kept constant by pacing the right atrium (Grass Instruments model S4G) with pulses of 1 msec at an effective voltage of 1.5 to 2.5 v. Experimental procedure: After control observations were recorded, the coronary artery was occluded by a May-
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PRACTOLDL AND W
clMENsloNs Dtmw
l6cHEMlA--LMvEN
MCLcf
mm
MCLDesc mm
FIGURE 1. Dog 2. Effects of practolol during occlusion of the left anterior descending coronary artery. Recordings of local myocardiil chord lengths (MCL) in the ventricular region supplied by the occluded left anterior descending coronary artery (Desc) and by the left circumflex coronary artery (Cf), which was not occluded. Upper margin of tracing denotes the enddffstolic myocardiil chord length.
Stroke
volume
ml/beat u t
Occlusion
1
f
Practolol
min
Occlusion Control
Occlusion Prac;olol
Aortic
flow
Vmin
MCLDesc mm
FIGURE 2. Dog 6. Pattern of myocardffl shortening during occlusion of the left anterior descending coronary artery before and after administration of practolol. Local myocardial chord lengths (MCL) were recorded in the ventricular region supplied by the descending artery @SC) and by the nonoccluded left circumflex coronary artery (Cf).
M%f mm
CKec
field clip. Redetermination of ventricular dimensions, pressures and flow was performed 3 to 5 minutes after occlusion. Then 10 to 20 mg of practolol (Eraldin, Imperial Chemical Industries, London) was given intravenously over 1 to 3 minutes, and new determinations were made 10 minutes after administration of practolol. All recordings were made during steady hemodynamic conditions. Immediately after the dogs were killed by administration of an overdose of sodium pentobarbital, Evans blue dye was injected into the coronary artery at the site of former occlusion and colored tissue was isolated and weighed. On average, 34.3 percent of left ventricular weight (range 21.8 to 41.5 percent) had been rendered ischemic by coronary occlusion. Statistical analysis: Each dog served as its own control. Student’s t test for paired data was used to calculate probability values (P).li A value of P >0.05 was regarded as not
statistically significant.
Results Tables I and II present the hemodynamic and dimensional effects of coronary arterial occlusion and
intravenous administration of practolol in nine dogs with spontaneous cardiac rhythm. Effects of coronary occlusion: Occlusion of the left anterior descending coronary artery was followed by marked end-diastolic dilatation in regions supplied by this artery (Fig. 1). Myocardial dilatation also occurred in nonischemic control regions supplied by the left circumflex coronary artery, and left ventricular end-diastolic pressure was increased by 2.8 f 0.5 mm Hg (P
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PBACTOLOL AN0 VENTBKXJLARDfMENStONSDURING ISCNEMIA-LEKVEN
15
n EDMCLDesc mm
% of control
12
value
6
10.00 1.00 SMSDesc mm 075
12 n EDMCL Ct % of cant rol
0.25
9
value
-
6 o-
1
I
Control
Occlusion
I
Occlusion Prac:olol
FIGURE 3. Effects of practolol during occlusion of the left anterior descending coronary artery in three dogs with a heart rate kept constant by right atrial pacing. End-diastolic myocardial chord length (EDMCL) and systolic myocardial shortening (SMS) were measured in ventricular regions supplied by the anterior descending artery (Desc).
0 LEFT
3
6
VENTRICULAR
PRESSURE,
9
12
END-DIASTOLIC
mm Hg
occlusion in most of the experiments (Fig. 1). In nonischemic control regions the systolic myocardial shortening remained unchanged during occlusion. Left uentricular performance was reduced by coronary occlusion, as evidenced by lower values for stroke volume, cardiac output, dP/dt and left ventricular systolic pressure (Table I). Effects of practolol: With the coronary artery still occluded, administration of practolol restored stroke volume almost to control levels, although dP/dt was further reduced (Table I). End-diastolic ventricular dimensions in nonischemic regions-and the end-diastolic ventricular pressure-increased further from the values obtained during occlusion alone, whereas the ischemic myocardial dilatation in occluded areas was reduced; however, control levels were not regained during beta adrenergic blockade in any experiment. Practolol diminished the early diastolic myocardial shortening in occluded areas, and a significantly greater portion of shortening occurred in ventricular systole (Fig. 2). In nonischemic regions practolol gave an opposite effect by reducing systolic myocardial shortening (Table II).
Left ventricular systolic pressure remained unchanged during beta adrenergic blockade with practolol. Cardiac output was reduced by 161 f 47 ml/ min (P
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FIGURE 4. Relation between left ventricular enddiastolic pressure and changes in end-diastolic myocardial chord length (AEDMCL). A, measurements from ventricular regions supplied by the occluded left anterior descending coronary artery (Desc). B, measurements from control regions supplied by the nonoccluded left circumflex coronary artery (Cf) Open circles = prior to occlusion; closed circles = during occlusion: triangles = after administration of practolol.
PRACTDLDL AND VENTFtWlAR DIMNSIONS DURING ISCI-EMIA-LEKVEN
regions increased by an average of 6.1 f 0.9 percent of control value after coronary occlusion, whereas nonischemic chord length increased by only 2.7 f 0.4 percent (Table II). Although left ventricular end-diastolic pressure was not similarly increased in individual experiments (Fig. 4), the highly significant difference in regional dimensions (P
Discussion Practolol and increased systolic myocardial shortening: The most important finding in this investigation was that practolol increased systolic myocardial shortening, which had been largely reduced by coronary occlusion. Although variable effects of practolol on stroke volume and contractility have previously been reported,4J2 left ventricular dP/dt and systolic myocardial shortening in nonischemic control regions were clearly reduced by practolol in this study. It is therefore reasonable to attribute restoration of stroke volume to an increased myocardial shortening in the ischemic regions. This represents an obvious improvement of ventricular function by practolol during acute coronary occlusion.
Practolol and improved myocardial oxygen balance: It is generally believed that practolol does
not increase myocardial oxygen supplies13 but diminishes net myocardial oxygen requirements through reduction in the contractile state and heart rate,5*6 although an accompanying ventricular dilatation7 might increase the myocardial oxygen demands.* Recent studies314 have revealed that S-T segment changes after coronary occlusion in dogs and myocardial infarction in patients were reduced by practolol, indicating an improved myocardial oxygen balance. Since a close relation between myocardial oxygen consumption and ventricular dilatation has been demonstrated during graded myocardial ischemia,g reduced ischemic dilatation by practolol indicates improved myocardial oxygen balance. A negative chronotropic action of practolol undoubtedly reduces myocardial oxygen demands.* However, since improved function of the ischemic myocardium could be demonstrated during constant atria1 pacing, reduced end-diastolic dimensions and wall tension8pg might also represent a reduction in the myocardial oxygen requirements, thus permitting increased systolic shortening. Thus, in addition to the antidysrhythmic properties of practolol, its ability to improve myocardial oxygen balance through these
End Diastolic Myocardial Dimensions
Left
ventricular
end-diastolic
pressure FIGURE 5. Scheme, calculated from the mean values in Figure 4, of the ventricular pressure/dimension relation in ventricular regions rendered ischemic by coronary arterial occlusion and in nonischemic control regions. Open circles = prior to occlusion; closed circles = during occlusion: triangles = after administration of practolol.
mechanisms constitutes the rationale for use of this agent in patients with acute myocardial infarction.
Practolol and redistribution of blood flow: A relative redistribution
myocardial
of coronary blood flow to ischemic areas has been demonstrated after administration of propranolol to hearts with occluded coronary arteries. l4 If such a mechanism also applies to practolol, this could contribute to improved myocardial oxygen balance and function, mainly in ischemic subendocardial layers. The demonstration in this study that improvement of mechanical function within the ischemic third of the left ventricle after beta adrenergic blockade is associated with concomitant reductions of systolic myocardial shortening within the nonischemic two thirds, ventricular contractility as a whole and dP/dt might be explained by redistribution of myocardial blood flow.
Practolol and improved myocardial metabolism: On the other hand, could myocardial oxygen
balance also be improved by beta adrenergic blocking agents through metabolic mechanisms? It has been demonstrated that antilipolytic agents reduce S-T segment elevation after acute coronary occlusion,15 probably by inhibiting myocardial lipolysis evoked by release of endogenous catecholamines in acutely ischemic tissue16 and leading to a relatively oxygenexpensive consumption of free fatty acids. Antilipolytic activity of practolol has been demonstrated in isolated fat cells17 and, if this applies also to in vivo myocardial oxygen requiremyocardial lipolysis, ments might thus be reduced in acutely ischemic myocardial tissue. Furthermore, it has recently been reportedI* that beta adrenergic blockade with propranolol permitted enhanced glycogenolytic energy production during anoxia in rat hearts. Thus, several mechanisms for improvement of myocardial oxygen balance by beta adrenergic block-
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PRACTOLOL AND VENTRlCU_AR lX&UONS
DLRING SCHEMIA-LEKVEN
ing agents are proposed although it is not known which is the most important or why oxygen requirements of ischemic myocardial tissue are reduced if increased blood supply may be present. Although these measurements provide no direct information on myocardial oxygen balance, they indicate that the mechanical function of the acutely ischemic myocardium benefits from beta adrenergic blockade by practolol. Practolol and changes in myocardial compliance: Use of left ventricular end-diastolic pressure
measurements to assess cardiac failure has among its limitations dependence on a constant ventricular relation.1gp20 Whereas increased pressure/volume end-diastolic pressure during coronary heart disease is commonly interpreted as an indication of incipient heart failure, the measurements reported here describe a situation after administration of practolol in which improved function of acutely ischemic myocardial tissue is associated with increased ventricular end-diastolic pressure. This finding thus emphasizes the reservations to use of ventricular end-diastolic pressure as a reliable index of ischemia or heart failure. Decreased ventricular compliance has been demonstrated in patients within a few days of myocardial infarction and in patients with chronic coronary artery disease.21 However, the observations in this study suggest an increased ventricular compliance in end-diastole in the ischemic regions immediately
after coronary occlusion. Compliance is defined as dV/dP, where V is volume of the left ventricle and P its intracavitary pressure. Since myocardial chord length increased significantly more within ischemic regions than within control regions, dV/dP must be greater in ischemic areas because the two regions have identical-and increased-ventricular pressures. Although ventricular pressure and dimensions were obtained during steady hemodynamic conditions, they were measured within the time limit of 20 to 30 minutes for development of irreversible cell injury. 22 It is therefore credible that after acute coronary occlusion compliance is initially increased in affected ventricular regions and later decreased, a change that might be explained by the pathologicanatomic alterations and cell death in the early healing phase.23 The observations in this study also indicate that practolol normalizes the increased compliance during acute ischemia. This finding implies that the ischemic myocardial tissue becomes capable of operating a more propitious Frank-Starling curve after beta adrenergic blockade, as was indicated by increased systolic shortening and stroke volume ejection after administration of practolol. Acknowledgment I thank Mrs. Grethe Laerum and Erik Holgersen, engineer, for their skilled technical assistance, and Mrs. Monica Hyde for help in the preparation and typing of the manuscript.
References 1. Jewltt DE, Burgess PA, Shillingford JP: The circulatory effects of practolol (ICI 50 172) in patients with acute myocardial infarction. Cardiovasc Res 4: 188-193, 1970 2. Dunlop D, Shanks RG: Selective blockade of adrenoceptive beta receptors in the heart. Br J Pharmacol Chemother 32: 201-218, 1968 3. Pelldes LJ, Reid DS, Thomas M, et al: Inhibition by &blockade of the ST segment elevation after acute myocardiil infarction in man. Cardiovasc Res 6:295-301, 1972 4. Llbby P, Maroko PR, Covell JW, et al: Effect of practolol on the extent of myocardial ischaemic injury after experimental coronary occlusion and its effects on ventricular function in the normal and ischaemic heart. Cardiovasc Res 7: 167- 173, 1973 5. Epstein SE, Braunwald E: Beta-adrenergic receptor blocking drugs. Mechanisms of action and clinical applications. N Engl J Med275:1106-1112, 1966 6. Ek L, Ablad B: Effects of three beta adrenergic receptor blockers on myocardial oxygen consumption in the dog. Eur J Pharmacol 14:19-28, 1971 7. Chamberlain DA: Effects of beta adrenergic blockade on heart size. Am J Cardiol 18:321-328, 1986 8. Bonnenbllck EH, Ross J Jr, BraunwakJ E: Oxygen consumption of the heart. Newer concepts of its multifactoral determination. Am J Cardiol 22:328-336, 1968 9. Lekven J, Mj#a OD, Kjekshus JK: Compensatory mechanisms during graded myocardial ischemia. Am J Cardiol 31:467-473, 1973 10. Lekven J, Bugge-Asperhelm B, Kill F: Relationship between local myocardial dimensions and left ventricular volume in dogs. Stand J Clin Lab Invest 295-14, 1972 11. Snedeoor GW, Cochran WG: Statistical Methods (sixth adiiion). Ames, Iowa, The Iowa State University Press, 1967, p 59-62 12. Flnegan RE, Marlon AM, Harrlaon DC: Circulatory effects of practolol. Am J Cardiol 29:315-322, 1972
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13. Ross G, Jorgensen CR: Effects of a cardio-selective beta-adrenergic blocking agent on the heart and coronary circulation. Cardiovasc Res 4: 148- 153. 1970 14. Becker L, Pitt B: Regional myocardial blood flow, ischemia and antianginal drugs. Ann Clin Res 3:353-361, 197 1 15. KJekshus JK, Mj+a OD: Effect of inhibition of lipolysis on infarct size after experimental coronary artery occlusion. J Clin Invest 5211770-1778, 1973 16. Wollenberger A, Krause E-G, Shahab L: Endogeneous catecholamine mobilization and the shift to anaerobic energy production in the acutely ischemic myocardium. In. Coronary Circulation and Energetics of the Myocardium (Marchetti G, Taccardi B, ed). Base1 and New York, Karger, 1967. p 200-219 17. Miller DW, Allen Ml: Antilipolytic activity of 4-(2-hydroxy-3-isopropylaminopropoxy) acetanilkie (practolol). Proc Sot Exp Biol Med 136:715-718, 1971 18. Chrlatodoulou J, Smtthen C, Frlschman W, et al: Protective role of increased myocardial glycogen stores induced by propranolol. (abstr). Proceedings VII World Congress of Cardiology, Buenos Aires, 1974. no 136 19. Braunwald E, Ross J Jr: The ventricular end-diastolic pressure. Appraisal of its value in the recognition of ventricular failure in man. Am J Med 34:147-150, 1963 20. Covell JW, Ross J Jr: Nature and significance of alterations in myocardial compliance. Am J Cardiol 32:449-455, 1973 2 I. Mamond 0, Forrester JS: Effect of coronary artery disease and acute myocardial infarction on left ventricular compliance in man. Circulation 45:11-19. 1972 22. Jennings RB: Early phase of myocardial ischemic injury and infarction. Am J Cardiol 24:753-765, 1969 23. Hood WB Jr, Blanc0 JA, Kumar R, et al: Experimental myocardial infarction. IV. Reduction of left ventricular compliance in the healing phase. J Clin Invest 49:1316-1323. 1970
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